PLOS Biology: New ArticlesPLOShttp://www.plosbiology.org/webmaster@plos.orgPublishing scienceinfo:doi/10.1371/feed.pbioThis work is licensed under a Creative Commons Attribution-Share Alike 3.0 Licensehttp://www.plosbiology.org/${webserver-url}images/favicon.icohttp://www.plosbiology.org/${webserver-url}images/favicon.ico2015-08-02T20:18:17ZSubscribe with My Yahoo!Subscribe with NewsGatorSubscribe with My AOLSubscribe with BloglinesSubscribe with NetvibesSubscribe with GoogleSubscribe with PageflakesWhere Next for Genetics and Genomics?Chris Tyler-Smith et al.info:doi/10.1371/journal.pbio.10022162015-07-30T21:00:00Z2015-07-30T21:00:00Z<p>by Chris Tyler-Smith, Huanming Yang, Laura F. Landweber, Ian Dunham, Bartha M. Knoppers, Peter Donnelly, Elaine R. Mardis, Michael Snyder, Gil McVean</p>
The last few decades have utterly transformed genetics and genomics, but what might the next ten years bring? <i>PLOS Biology</i> asked eight leaders spanning a range of related areas to give us their predictions. Without exception, the predictions are for more data on a massive scale and of more diverse types. All are optimistic and predict enormous positive impact on scientific understanding, while a recurring theme is the benefit of such data for the transformation and personalization of medicine. Several also point out that the biggest changes will very likely be those that we don’t foresee, even now.<img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/Q1Mfkdyhjzw" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002216CDK8-Cyclin C Mediates Nutritional Regulation of Developmental Transitions through the Ecdysone Receptor in DrosophilaXiao-Jun Xie et al.info:doi/10.1371/journal.pbio.10022072015-07-29T21:00:00Z2015-07-29T21:00:00Z<p>by Xiao-Jun Xie, Fu-Ning Hsu, Xinsheng Gao, Wu Xu, Jian-Quan Ni, Yue Xing, Liying Huang, Hao-Ching Hsiao, Haiyan Zheng, Chenguang Wang, Yani Zheng, Alus M. Xiaoli, Fajun Yang, Sarah E. Bondos, Jun-Yuan Ji</p>
The steroid hormone ecdysone and its receptor (EcR) play critical roles in orchestrating developmental transitions in arthropods. However, the mechanism by which EcR integrates nutritional and developmental cues to correctly activate transcription remains poorly understood. Here, we show that EcR-dependent transcription, and thus, developmental timing in <i>Drosophila</i>, is regulated by CDK8 and its regulatory partner Cyclin C (CycC), and the level of CDK8 is affected by nutrient availability. We observed that <i>cdk8</i> and <i>cycC</i> mutants resemble EcR mutants and EcR-target genes are systematically down-regulated in both mutants. Indeed, the ability of the EcR-Ultraspiracle (USP) heterodimer to bind to polytene chromosomes and the promoters of EcR target genes is also diminished. Mass spectrometry analysis of proteins that co-immunoprecipitate with EcR and USP identified multiple Mediator subunits, including CDK8 and CycC. Consistently, CDK8-CycC interacts with EcR-USP in vivo; in particular, CDK8 and Med14 can directly interact with the AF1 domain of EcR. These results suggest that CDK8-CycC may serve as transcriptional cofactors for EcR-dependent transcription. During the larval–pupal transition, the levels of CDK8 protein positively correlate with EcR and USP levels, but inversely correlate with the activity of sterol regulatory element binding protein (SREBP), the master regulator of intracellular lipid homeostasis. Likewise, starvation of early third instar larvae precociously increases the levels of CDK8, EcR and USP, yet down-regulates SREBP activity. Conversely, refeeding the starved larvae strongly reduces CDK8 levels but increases SREBP activity. Importantly, these changes correlate with the timing for the larval–pupal transition. Taken together, these results suggest that CDK8-CycC links nutrient intake to developmental transitions (EcR activity) and fat metabolism (SREBP activity) during the larval–pupal transition.<img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/83V-2jowpWk" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002207Extracting Environmental Benefits from a New Canal in Nicaragua: Lessons from PanamaRichard Conditinfo:doi/10.1371/journal.pbio.10022082015-07-27T21:00:00Z2015-07-27T21:00:00Z<p>by Richard Condit</p>
Biologists have raised objections to a new canal in Nicaragua, but in this Essay I argue that dire predictions of environmental catastrophe are exaggerated. I present an alternative view based on my research experience in Panama, where Canal operations foster forest conservation. Currently in Nicaragua, the rate of forest loss is so rapid that the canal cannot make it worse. Rather, I contend, adoption of international standards in canal construction could lead to net environmental and social benefits for the country.<img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/t3ikNKXo1SE" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002208Imperfect Vaccination Can Enhance the Transmission of Highly Virulent PathogensAndrew F. Read et al.info:doi/10.1371/journal.pbio.10021982015-07-27T21:00:00Z2015-07-27T21:00:00Z<p>by Andrew F. Read, Susan J. Baigent, Claire Powers, Lydia B. Kgosana, Luke Blackwell, Lorraine P. Smith, David A. Kennedy, Stephen W. Walkden-Brown, Venugopal K. Nair</p>
Could some vaccines drive the evolution of more virulent pathogens? Conventional wisdom is that natural selection will remove highly lethal pathogens if host death greatly reduces transmission. Vaccines that keep hosts alive but still allow transmission could thus allow very virulent strains to circulate in a population. Here we show experimentally that immunization of chickens against Marek's disease virus enhances the fitness of more virulent strains, making it possible for hyperpathogenic strains to transmit. Immunity elicited by direct vaccination or by maternal vaccination prolongs host survival but does not prevent infection, viral replication or transmission, thus extending the infectious periods of strains otherwise too lethal to persist. Our data show that anti-disease vaccines that do not prevent transmission can create conditions that promote the emergence of pathogen strains that cause more severe disease in unvaccinated hosts.<img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/Vaq5LSdKHN8" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002198Let's Make Gender Diversity in Data Science a Priority Right from the StartFrancine D. Berman et al.info:doi/10.1371/journal.pbio.10022062015-07-27T21:00:00Z2015-07-27T21:00:00Z<p>by Francine D. Berman, Philip E. Bourne</p>
The emergent field of data science is a critical driver for innovation in all sectors, a focus of tremendous workforce development, and an area of increasing importance within science, technology, engineering, and math (STEM). In all of its aspects, data science has the potential to narrow the gender gap and set a new bar for inclusion. To evolve data science in a way that promotes gender diversity, we must address two challenges: (1) how to increase the number of women acquiring skills and working in data science and (2) how to evolve organizations and professional cultures to better retain and advance women in data science. Everyone can contribute.<img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/lmrmJeIuLp0" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002206Diffusion Magnetic Resonance Imaging: What Water Tells Us about Biological TissuesDenis Le Bihan et al.info:doi/10.1371/journal.pbio.10022032015-07-23T21:00:00Z2015-07-23T21:00:00Z<p>by Denis Le Bihan, Mami Iima</p>
Since its introduction in the mid-1980s, diffusion magnetic resonance imaging (MRI), which measures the random motion of water molecules in tissues, revealing their microarchitecture, has become a pillar of modern neuroimaging. Its main clinical domain has been the diagnosis of acute brain stroke and neurogical disorders, but it is also used in the body for the detection and management of cancer lesions. It can also produce stunning maps of white matter tracks in the brain, with the potential to aid in the understanding of some psychiatric disorders. However, in order to exploit fully the potential of this method, a deeper understanding of the mechanisms that govern the diffusion of water in tissues is needed.<img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/85lm1PhUzVk" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002203The Importance of Biodiversity E-infrastructures for Megadiverse CountriesDora A. L. Canhos et al.info:doi/10.1371/journal.pbio.10022042015-07-23T21:00:00Z2015-07-23T21:00:00Z<p>by Dora A. L. Canhos, Mariane S. Sousa-Baena, Sidnei de Souza, Leonor C. Maia, João R. Stehmann, Vanderlei P. Canhos, Renato De Giovanni, Maria B. M. Bonacelli, Wouter Los, A. Townsend Peterson</p>
Addressing the challenges of biodiversity conservation and sustainable development requires global cooperation, support structures, and new governance models to integrate diverse initiatives and achieve massive, open exchange of data, tools, and technology. The traditional paradigm of sharing scientific knowledge through publications is not sufficient to meet contemporary demands that require not only the results but also data, knowledge, and skills to analyze the data. E-infrastructures are key in facilitating access to data and providing the framework for collaboration. Here we discuss the importance of e-infrastructures of public interest and the lack of long-term funding policies. We present the example of Brazil’s <i>species</i>Link network, an e-infrastructure that provides free and open access to biodiversity primary data and associated tools. <i>Species</i>Link currently integrates 382 datasets from 135 national institutions and 13 institutions from abroad, openly sharing ~7.4 million records, 94% of which are associated to voucher specimens. Just as important as the data is the network of data providers and users. In 2014, more than 95% of its users were from Brazil, demonstrating the importance of local e-infrastructures in enabling and promoting local use of biodiversity data and knowledge. From the outset, <i>species</i>Link has been sustained through project-based funding, normally public grants for 2–4-year periods. In between projects, there are short-term crises in trying to keep the system operational, a fact that has also been observed in global biodiversity portals, as well as in social and physical sciences platforms and even in computing services portals. In the last decade, the open access movement propelled the development of many web platforms for sharing data. Adequate policies unfortunately did not follow the same tempo, and now many initiatives may perish.<img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/ABvJ8o8EyRM" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002204The Functional Connectome of Speech ControlStefan Fuertinger et al.info:doi/10.1371/journal.pbio.10022092015-07-23T21:00:00Z2015-07-23T21:00:00Z<p>by Stefan Fuertinger, Barry Horwitz, Kristina Simonyan</p>
In the past few years, several studies have been directed to understanding the complexity of functional interactions between different brain regions during various human behaviors. Among these, neuroimaging research installed the notion that speech and language require an orchestration of brain regions for comprehension, planning, and integration of a heard sound with a spoken word. However, these studies have been largely limited to mapping the neural correlates of separate speech elements and examining distinct cortical or subcortical circuits involved in different aspects of speech control. As a result, the complexity of the brain network machinery controlling speech and language remained largely unknown. Using graph theoretical analysis of functional MRI (fMRI) data in healthy subjects, we quantified the large-scale speech network topology by constructing functional brain networks of increasing hierarchy from the resting state to motor output of meaningless syllables to complex production of real-life speech as well as compared to non-speech-related sequential finger tapping and pure tone discrimination networks. We identified a segregated network of highly connected local neural communities (hubs) in the primary sensorimotor and parietal regions, which formed a commonly shared core hub network across the examined conditions, with the left area 4p playing an important role in speech network organization. These sensorimotor core hubs exhibited features of flexible hubs based on their participation in several functional domains across different networks and ability to adaptively switch long-range functional connectivity depending on task content, resulting in a distinct community structure of each examined network. Specifically, compared to other tasks, speech production was characterized by the formation of six distinct neural communities with specialized recruitment of the prefrontal cortex, insula, putamen, and thalamus, which collectively forged the formation of the functional speech connectome. In addition, the observed capacity of the primary sensorimotor cortex to exhibit operational heterogeneity challenged the established concept of unimodality of this region.<img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/I3wcFxVP8uE" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002209The Orphan Nuclear Receptor TLX Is an Enhancer of STAT1-Mediated Transcription and Immunity to Toxoplasma gondiiDaniel P. Beiting et al.info:doi/10.1371/journal.pbio.10022002015-07-21T21:00:00Z2015-07-21T21:00:00Z<p>by Daniel P. Beiting, Shinya Hidano, Julie E. Baggs, Jeanne M. Geskes, Qun Fang, E. John Wherry, Christopher A. Hunter, David S. Roos, Sara Cherry</p>
The protozoan parasite, <i>Toxoplasma</i>, like many intracellular pathogens, suppresses interferon gamma (IFN-γ)-induced signal transducer and activator of transcription 1 (STAT1) activity. We exploited this well-defined host–pathogen interaction as the basis for a high-throughput screen, identifying nine transcription factors that enhance STAT1 function in the nucleus, including the orphan nuclear hormone receptor TLX. Expression profiling revealed that upon IFN-γ treatment TLX enhances the output of a subset of IFN-γ target genes, which we found is dependent on TLX binding at those loci. Moreover, infection of TLX deficient mice with the intracellular parasite <i>Toxoplasma</i> results in impaired production of the STAT1-dependent cytokine interleukin-12 by dendritic cells and increased parasite burden in the brain during chronic infection. These results demonstrate a previously unrecognized role for this orphan nuclear hormone receptor in regulating STAT1 signaling and host defense and reveal that STAT1 activity can be modulated in a context-specific manner by such “modifiers.”<img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/JjtC6xByjBo" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002200Tuning up STAT1Caitlin Sedwickinfo:doi/10.1371/journal.pbio.10022012015-07-21T21:00:00Z2015-07-21T21:00:00Z<p>by Caitlin Sedwick</p><img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/oz3xTEMR48g" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002201Retraction: Neutralizing Aptamers from Whole-Cell SELEX Inhibit the RET Receptor Tyrosine KinaseLaura Cerchia et al.info:doi/10.1371/journal.pbio.10022152015-07-17T21:00:00Z2015-07-17T21:00:00Z<p>by Laura Cerchia, Frédéric Ducongé, Carine Pestourie, Jocelyne Boulay, Youssef Aissouni, Karine Gombert, Bertrand Tavitian, Vittorio de Franciscis, Domenico Libri</p><img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/BeD2HXOObH0" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002215Lactate Regulates Metabolic and Pro-inflammatory Circuits in Control of T Cell Migration and Effector FunctionsRobert Haas et al.info:doi/10.1371/journal.pbio.10022022015-07-16T21:00:00Z2015-07-16T21:00:00Z<p>by Robert Haas, Joanne Smith, Vidalba Rocher-Ros, Suchita Nadkarni, Trinidad Montero-Melendez, Fulvio D’Acquisto, Elliot J. Bland, Michele Bombardieri, Costantino Pitzalis, Mauro Perretti, Federica M. Marelli-Berg, Claudio Mauro</p>
Lactate has long been considered a “waste” by-product of cell metabolism, and it accumulates at sites of inflammation. Recent findings have identified lactate as an active metabolite in cell signalling, although its effects on immune cells during inflammation are largely unexplored. Here we ask whether lactate is responsible for T cells remaining entrapped in inflammatory sites, where they perpetuate the chronic inflammatory process. We show that lactate accumulates in the synovia of rheumatoid arthritis patients. Extracellular sodium lactate and lactic acid inhibit the motility of CD4<sup>+</sup> and CD8<sup>+</sup> T cells, respectively. This selective control of T cell motility is mediated via subtype-specific transporters (Slc5a12 and Slc16a1) that we find selectively expressed by CD4<sup>+</sup> and CD8<sup>+</sup> subsets, respectively. We further show both in vitro and in vivo that the sodium lactate-mediated inhibition of CD4<sup>+</sup> T cell motility is due to an interference with glycolysis activated upon engagement of the chemokine receptor CXCR3 with the chemokine CXCL10. In contrast, we find the lactic acid effect on CD8<sup>+</sup> T cell motility to be independent of glycolysis control. In CD4<sup>+</sup> T helper cells, sodium lactate also induces a switch towards the Th17 subset that produces large amounts of the proinflammatory cytokine IL-17, whereas in CD8<sup>+</sup> T cells, lactic acid causes the loss of their cytolytic function. We further show that the expression of lactate transporters correlates with the clinical T cell score in the synovia of rheumatoid arthritis patients. Finally, pharmacological or antibody-mediated blockade of subtype-specific lactate transporters on T cells results in their release from the inflammatory site in an in vivo model of peritonitis. By establishing a novel role of lactate in control of proinflammatory T cell motility and effector functions, our findings provide a potential molecular mechanism for T cell entrapment and functional changes in inflammatory sites that drive chronic inflammation and offer targeted therapeutic interventions for the treatment of chronic inflammatory disorders.<img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/aMHYssKDtMA" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002202Impaired Mitochondrial Energy Production Causes Light-Induced Photoreceptor Degeneration Independent of Oxidative StressManish Jaiswal et al.info:doi/10.1371/journal.pbio.10021972015-07-15T21:00:00Z2015-07-15T21:00:00Z<p>by Manish Jaiswal, Nele A. Haelterman, Hector Sandoval, Bo Xiong, Taraka Donti, Auinash Kalsotra, Shinya Yamamoto, Thomas A. Cooper, Brett H. Graham, Hugo J. Bellen</p>
Two insults often underlie a variety of eye diseases including glaucoma, optic atrophy, and retinal degeneration—defects in mitochondrial function and aberrant Rhodopsin trafficking. Although mitochondrial defects are often associated with oxidative stress, they have not been linked to Rhodopsin trafficking. In an unbiased forward genetic screen designed to isolate mutations that cause photoreceptor degeneration, we identified mutations in a nuclear-encoded mitochondrial gene, <i>ppr</i>, a homolog of human <i>LRPPRC</i>. We found that <i>ppr</i> is required for protection against light-induced degeneration. Its function is essential to maintain membrane depolarization of the photoreceptors upon repetitive light exposure, and an impaired phototransduction cascade in <i>ppr</i> mutants results in excessive Rhodopsin1 endocytosis. Moreover, loss of <i>ppr</i> results in a reduction in mitochondrial RNAs, reduced electron transport chain activity, and reduced ATP levels. Oxidative stress, however, is not induced. We propose that the reduced ATP level in <i>ppr</i> mutants underlies the phototransduction defect, leading to increased Rhodopsin1 endocytosis during light exposure, causing photoreceptor degeneration independent of oxidative stress. This hypothesis is bolstered by characterization of two other genes isolated in the screen, <i>pyruvate dehydrogenase</i> and <i>citrate synthase</i>. Their loss also causes a light-induced degeneration, excessive Rhodopsin1 endocytosis and reduced ATP without concurrent oxidative stress, unlike many other mutations in mitochondrial genes that are associated with elevated oxidative stress and light-independent photoreceptor demise.<img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/R8JYQVvh0Z0" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002197The Discovery, Distribution, and Evolution of Viruses Associated with Drosophila melanogasterClaire L. Webster et al.info:doi/10.1371/journal.pbio.10022102015-07-14T21:00:00Z2015-07-14T21:00:00Z<p>by Claire L. Webster, Fergal M. Waldron, Shaun Robertson, Daisy Crowson, Giada Ferrari, Juan F. Quintana, Jean-Michel Brouqui, Elizabeth H. Bayne, Ben Longdon, Amy H. Buck, Brian P. Lazzaro, Jewelna Akorli, Penelope R. Haddrill, Darren J. Obbard</p>
<i>Drosophila melanogaster</i> is a valuable invertebrate model for viral infection and antiviral immunity, and is a focus for studies of insect-virus coevolution. Here we use a metagenomic approach to identify more than 20 previously undetected RNA viruses and a DNA virus associated with wild <i>D</i>. <i>melanogaster</i>. These viruses not only include distant relatives of known insect pathogens but also novel groups of insect-infecting viruses. By sequencing virus-derived small RNAs, we show that the viruses represent active infections of <i>Drosophila</i>. We find that the RNA viruses differ in the number and properties of their small RNAs, and we detect both siRNAs and a novel miRNA from the DNA virus. Analysis of small RNAs also allows us to identify putative viral sequences that lack detectable sequence similarity to known viruses. By surveying >2,000 individually collected wild adult <i>Drosophila</i> we show that more than 30% of <i>D</i>. <i>melanogaster</i> carry a detectable virus, and more than 6% carry multiple viruses. However, despite a high prevalence of the <i>Wolbachia</i> endosymbiont—which is known to be protective against virus infections in <i>Drosophila</i>—we were unable to detect any relationship between the presence of <i>Wolbachia</i> and the presence of any virus. Using publicly available RNA-seq datasets, we show that the community of viruses in <i>Drosophila</i> laboratories is very different from that seen in the wild, but that some of the newly discovered viruses are nevertheless widespread in laboratory lines and are ubiquitous in cell culture. By sequencing viruses from individual wild-collected flies we show that some viruses are shared between <i>D</i>. <i>melanogaster</i> and <i>D</i>. <i>simulans</i>. Our results provide an essential evolutionary and ecological context for host–virus interaction in <i>Drosophila</i>, and the newly reported viral sequences will help develop <i>D</i>. <i>melanogaster</i> further as a model for molecular and evolutionary virus research.<img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/vNz5Ad2iRbw" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002210Auditory Processing in Noise: A Preschool Biomarker for LiteracyTravis White-Schwoch et al.info:doi/10.1371/journal.pbio.10021962015-07-14T21:00:00Z2015-07-14T21:00:00Z<p>by Travis White-Schwoch, Kali Woodruff Carr, Elaine C. Thompson, Samira Anderson, Trent Nicol, Ann R. Bradlow, Steven G. Zecker, Nina Kraus</p>
Learning to read is a fundamental developmental milestone, and achieving reading competency has lifelong consequences. Although literacy development proceeds smoothly for many children, a subset struggle with this learning process, creating a need to identify reliable biomarkers of a child’s future literacy that could facilitate early diagnosis and access to crucial early interventions. Neural markers of reading skills have been identified in school-aged children and adults; many pertain to the precision of information processing in noise, but it is unknown whether these markers are present in pre-reading children. Here, in a series of experiments in 112 children (ages 3–14 y), we show brain–behavior relationships between the integrity of the neural coding of speech in noise and phonology. We harness these findings into a predictive model of preliteracy, revealing that a 30-min neurophysiological assessment predicts performance on multiple pre-reading tests and, one year later, predicts preschoolers’ performance across multiple domains of emergent literacy. This same neural coding model predicts literacy and diagnosis of a learning disability in school-aged children. These findings offer new insight into the biological constraints on preliteracy during early childhood, suggesting that neural processing of consonants in noise is fundamental for language and reading development. Pragmatically, these findings open doors to early identification of children at risk for language learning problems; this early identification may in turn facilitate access to early interventions that could prevent a life spent struggling to read.<img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/ZIZ_CGlSQYI" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002196Correction: Phosphorylation of Mouse Immunity-Related GTPase (IRG) Resistance Proteins Is an Evasion Strategy for Virulent Toxoplasma gondiiTobias Steinfeldt et al.info:doi/10.1371/journal.pbio.10021992015-07-09T21:00:00Z2015-07-09T21:00:00Z<p>by Tobias Steinfeldt, Stephanie Könen-Waisman, Lan Tong, Nikolaus Pawlowski, Tobias Lamkemeyer, L. David Sibley, Julia P. Hunn, Jonathan C. Howard</p><img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/J2untEBiU_E" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002199Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB1 and Serotonin 5-HT2A ReceptorsXavier Viñals et al.info:doi/10.1371/journal.pbio.10021942015-07-09T21:00:00Z2015-07-09T21:00:00Z<p>by Xavier Viñals, Estefanía Moreno, Laurence Lanfumey, Arnau Cordomí, Antoni Pastor, Rafael de La Torre, Paola Gasperini, Gemma Navarro, Lesley A. Howell, Leonardo Pardo, Carmen Lluís, Enric I. Canela, Peter J. McCormick, Rafael Maldonado, Patricia Robledo</p>
Activation of cannabinoid CB1 receptors (CB<sub>1</sub>R) by delta9-tetrahydrocannabinol (THC) produces a variety of negative effects with major consequences in cannabis users that constitute important drawbacks for the use of cannabinoids as therapeutic agents. For this reason, there is a tremendous medical interest in harnessing the beneficial effects of THC. Behavioral studies carried out in mice lacking 5-HT<sub>2A</sub> receptors (5-HT<sub>2A</sub>R) revealed a remarkable 5-HT<sub>2A</sub>R-dependent dissociation in the beneficial antinociceptive effects of THC and its detrimental amnesic properties. We found that specific effects of THC such as memory deficits, anxiolytic-like effects, and social interaction are under the control of 5-HT<sub>2A</sub>R, but its acute hypolocomotor, hypothermic, anxiogenic, and antinociceptive effects are not. In biochemical studies, we show that CB<sub>1</sub>R and 5-HT<sub>2A</sub>R form heteromers that are expressed and functionally active in specific brain regions involved in memory impairment. Remarkably, our functional data shows that costimulation of both receptors by agonists reduces cell signaling, antagonist binding to one receptor blocks signaling of the interacting receptor, and heteromer formation leads to a switch in G-protein coupling for 5-HT<sub>2A</sub>R from Gq to Gi proteins. Synthetic peptides with the sequence of transmembrane helices 5 and 6 of CB<sub>1</sub>R, fused to a cell-penetrating peptide, were able to disrupt receptor heteromerization in vivo, leading to a selective abrogation of memory impairments caused by exposure to THC. These data reveal a novel molecular mechanism for the functional interaction between CB<sub>1</sub>R and 5-HT<sub>2A</sub>R mediating cognitive impairment. CB<sub>1</sub>R-5-HT<sub>2A</sub>R heteromers are thus good targets to dissociate the cognitive deficits induced by THC from its beneficial antinociceptive properties.<img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/9RvMjDa44qY" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002194Selective Reduction of THC’s Unwanted Effects through Serotonin Receptor InhibitionRichard Robinsoninfo:doi/10.1371/journal.pbio.10021932015-07-09T21:00:00Z2015-07-09T21:00:00Z<p>by Richard Robinson</p><img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/6uG7WgqDZO0" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002193Single Turnover Autophosphorylation Cycle of the PKA RIIβ HoloenzymePing Zhang et al.info:doi/10.1371/journal.pbio.10021922015-07-09T21:00:00Z2015-07-09T21:00:00Z<p>by Ping Zhang, Matthias J. Knape, Lalima G. Ahuja, Malik M. Keshwani, Charles C. King, Mira Sastri, Friedrich W. Herberg, Susan S. Taylor</p>
To provide tight spatiotemporal signaling control, the cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) holoenzyme typically nucleates a macromolecular complex or a “PKA signalosome.” Using the RIIβ holoenzyme as a prototype, we show how autophosphorylation/dephosphorylation of the RIIβ subunit, as well as cAMP and metal ions, contribute to the dynamics of PKA signaling. While we showed previously that the RIIβ holoenzyme could undergo a single turnover autophosphorylation with adenosine triphosphate and magnesium (MgATP) and trap both products in the crystal lattice, we asked here whether calcium could trap an ATP:RIIβ holoenzyme since the RIIβ holoenzyme is located close to ion channels. The 2.8Å structure of an RIIβ<sup>p</sup><sub>2</sub>:C<sub>2</sub>:(Ca<sub>2</sub>ADP)<sub>2</sub> holoenzyme, supported by biochemical and biophysical data, reveals a trapped single phosphorylation event similar to MgATP. Thus, calcium can mediate a single turnover event with either ATP or adenosine-5'-(β,γ-imido)triphosphate (AMP-PNP), even though it cannot support steady-state catalysis efficiently. The holoenzyme serves as a “product trap” because of the slow off-rate of the pRIIβ subunit, which is controlled by cAMP, not by phosphorylation of the inhibitor site. By quantitatively defining the RIIβ signaling cycle, we show that release of pRIIβ in the presence of cAMP is reduced by calcium, whereas autophosphorylation at the phosphorylation site (P-site) inhibits holoenzyme reassociation with the catalytic subunit. Adding a single phosphoryl group to the preformed RIIβ holoenzyme thus creates a signaling cycle in which phosphatases become an essential partner. This previously unappreciated molecular mechanism is an integral part of PKA signaling for type II holoenzymes.<img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/rcTh1-fJQ6k" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002192Biofilm Formation As a Response to Ecological CompetitionNuno M. Oliveira et al.info:doi/10.1371/journal.pbio.10021912015-07-09T21:00:00Z2015-07-09T21:00:00Z<p>by Nuno M. Oliveira, Esteban Martinez-Garcia, Joao Xavier, William M. Durham, Roberto Kolter, Wook Kim, Kevin R. Foster</p>
Bacteria form dense surface-associated communities known as biofilms that are central to their persistence and how they affect us. Biofilm formation is commonly viewed as a cooperative enterprise, where strains and species work together for a common goal. Here we explore an alternative model: biofilm formation is a response to ecological competition. We co-cultured a diverse collection of natural isolates of the opportunistic pathogen <i>Pseudomonas aeruginosa</i> and studied the effect on biofilm formation. We show that strain mixing reliably increases biofilm formation compared to unmixed conditions. Importantly, strain mixing leads to strong competition: one strain dominates and largely excludes the other from the biofilm. Furthermore, we show that pyocins, narrow-spectrum antibiotics made by other <i>P</i>. <i>aeruginosa</i> strains, can stimulate biofilm formation by increasing the attachment of cells. Side-by-side comparisons using microfluidic assays suggest that the increase in biofilm occurs due to a general response to cellular damage: a comparable biofilm response occurs for pyocins that disrupt membranes as for commercial antibiotics that damage DNA, inhibit protein synthesis or transcription. Our data show that bacteria increase biofilm formation in response to ecological competition that is detected by antibiotic stress. This is inconsistent with the idea that sub-lethal concentrations of antibiotics are cooperative signals that coordinate microbial communities, as is often concluded. Instead, our work is consistent with competition sensing where low-levels of antibiotics are used to detect and respond to the competing genotypes that produce them.<img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/B3CdlWl7zds" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002191Evidence of Experimental Bias in the Life Sciences: Why We Need Blind Data RecordingLuke Holman et al.info:doi/10.1371/journal.pbio.10021902015-07-08T21:00:00Z2015-07-08T21:00:00Z<p>by Luke Holman, Megan L. Head, Robert Lanfear, Michael D. Jennions</p>
Observer bias and other “experimenter effects” occur when researchers’ expectations influence study outcome. These biases are strongest when researchers expect a particular result, are measuring subjective variables, and have an incentive to produce data that confirm predictions. To minimize bias, it is good practice to work “blind,” meaning that experimenters are unaware of the identity or treatment group of their subjects while conducting research. Here, using text mining and a literature review, we find evidence that blind protocols are uncommon in the life sciences and that nonblind studies tend to report higher effect sizes and more significant <i>p</i>-values. We discuss methods to minimize bias and urge researchers, editors, and peer reviewers to keep blind protocols in mind.<img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/o5-zIlIHaKU" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002190Big Data: Astronomical or Genomical?Zachary D. Stephens et al.info:doi/10.1371/journal.pbio.10021952015-07-07T21:00:00Z2015-07-07T21:00:00Z<p>by Zachary D. Stephens, Skylar Y. Lee, Faraz Faghri, Roy H. Campbell, Chengxiang Zhai, Miles J. Efron, Ravishankar Iyer, Michael C. Schatz, Saurabh Sinha, Gene E. Robinson</p>
Genomics is a Big Data science and is going to get much bigger, very soon, but it is not known whether the needs of genomics will exceed other Big Data domains. Projecting to the year 2025, we compared genomics with three other major generators of Big Data: astronomy, YouTube, and Twitter. Our estimates show that genomics is a “four-headed beast”—it is either on par with or the most demanding of the domains analyzed here in terms of data acquisition, storage, distribution, and analysis. We discuss aspects of new technologies that will need to be developed to rise up and meet the computational challenges that genomics poses for the near future. Now is the time for concerted, community-wide planning for the “genomical” challenges of the next decade.<img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/bgc3PvACLUk" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002195Glypican Is a Modulator of Netrin-Mediated Axon GuidanceCassandra R. Blanchette et al.info:doi/10.1371/journal.pbio.10021832015-07-06T21:00:00Z2015-07-06T21:00:00Z<p>by Cassandra R. Blanchette, Paola N. Perrat, Andrea Thackeray, Claire Y. Bénard</p>
Netrin is a key axon guidance cue that orients axon growth during neural circuit formation. However, the mechanisms regulating netrin and its receptors in the extracellular milieu are largely unknown. Here we demonstrate that in <i>Caenorhabditis elegans</i>, LON-2/glypican, a heparan sulfate proteoglycan, modulates UNC-6/netrin signaling and may do this through interactions with the UNC-40/DCC receptor. We show that developing axons misorient in the absence of LON-2/glypican when the SLT-1/slit guidance pathway is compromised and that LON-2/glypican functions in both the attractive and repulsive UNC-6/netrin pathways. We find that the core LON-2/glypican protein, lacking its heparan sulfate chains, and secreted forms of LON-2/glypican are functional in axon guidance. We also find that LON-2/glypican functions from the epidermal substrate cells to guide axons, and we provide evidence that LON-2/glypican associates with UNC-40/DCC receptor–expressing cells. We propose that LON-2/glypican acts as a modulator of UNC-40/DCC-mediated guidance to fine-tune axonal responses to UNC-6/netrin signals during migration.<img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/iVmSrgvdTNY" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002183Correction: The Challenging Road towards a Unified Animal Research Network in EuropeEmma Martinez-Sanchez et al.info:doi/10.1371/journal.pbio.10022052015-07-06T21:00:00Z2015-07-06T21:00:00Z<p>by Emma Martinez-Sanchez, Kirk Leech</p><img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/olq_RKxQgd4" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002205Far from Membranes, BEACH Domains Regulate Stress-Related mRNAsRichard Robinsoninfo:doi/10.1371/journal.pbio.10021892015-07-02T21:00:00Z2015-07-02T21:00:00Z<p>by Richard Robinson</p><img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/XHaCS2igqkQ" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002189The BEACH Domain Protein SPIRRIG Is Essential for Arabidopsis Salt Stress Tolerance and Functions as a Regulator of Transcript Stabilization and LocalizationAlexandra Steffens et al.info:doi/10.1371/journal.pbio.10021882015-07-02T21:00:00Z2015-07-02T21:00:00Z<p>by Alexandra Steffens, Andrea Bräutigam, Marc Jakoby, Martin Hülskamp</p>
Members of the highly conserved class of BEACH domain containing proteins (BDCPs) have been established as broad facilitators of protein–protein interactions and membrane dynamics in the context of human diseases like albinism, bleeding diathesis, impaired cellular immunity, cancer predisposition, and neurological dysfunctions. Also, the Arabidopsis thaliana BDCP SPIRRIG (SPI) is important for membrane integrity, as <i>spi</i> mutants exhibit split vacuoles. In this work, we report a novel molecular function of the BDCP SPI in ribonucleoprotein particle formation. We show that SPI interacts with the P-body core component DECAPPING PROTEIN 1 (DCP1), associates to mRNA processing bodies (P-bodies), and regulates their assembly upon salt stress. The finding that <i>spi</i> mutants exhibit salt hypersensitivity suggests that the local function of SPI at P-bodies is of biological relevance. Transcriptome-wide analysis revealed qualitative differences in the salt stress-regulated transcriptional response of Col-0 and <i>spi</i>. We show that SPI regulates the salt stress-dependent post-transcriptional stabilization, cytoplasmic agglomeration, and localization to P-bodies of a subset of salt stress-regulated mRNAs. Finally, we show that the PH-BEACH domains of SPI and its human homolog FAN (Factor Associated with Neutral sphingomyelinase activation) interact with DCP1 isoforms from plants, mammals, and yeast, suggesting the evolutionary conservation of an association of BDCPs and P-bodies.<img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/wfB4q8-9Ays" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002188Learning with the Spinal CordRichard Robinsoninfo:doi/10.1371/journal.pbio.10021872015-06-30T21:00:00Z2015-06-30T21:00:00Z<p>by Richard Robinson</p><img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/8PA243l9E1Q" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002187Simultaneous Brain–Cervical Cord fMRI Reveals Intrinsic Spinal Cord Plasticity during Motor Sequence LearningShahabeddin Vahdat et al.info:doi/10.1371/journal.pbio.10021862015-06-30T21:00:00Z2015-06-30T21:00:00Z<p>by Shahabeddin Vahdat, Ovidiu Lungu, Julien Cohen-Adad, Veronique Marchand-Pauvert, Habib Benali, Julien Doyon</p>
The spinal cord participates in the execution of skilled movements by translating high-level cerebral motor representations into musculotopic commands. Yet, the extent to which motor skill acquisition relies on intrinsic spinal cord processes remains unknown. To date, attempts to address this question were limited by difficulties in separating spinal local effects from supraspinal influences through traditional electrophysiological and neuroimaging methods. Here, for the first time, we provide evidence for local learning-induced plasticity in intact human spinal cord through simultaneous functional magnetic resonance imaging of the brain and spinal cord during motor sequence learning. Specifically, we show learning-related modulation of activity in the C6–C8 spinal region, which is independent from that of related supraspinal sensorimotor structures. Moreover, a brain–spinal cord functional connectivity analysis demonstrates that the initial linear relationship between the spinal cord and sensorimotor cortex gradually fades away over the course of motor sequence learning, while the connectivity between spinal activity and cerebellum gains strength. These data suggest that the spinal cord not only constitutes an active functional component of the human motor learning network but also contributes distinctively from the brain to the learning process. The present findings open new avenues for rehabilitation of patients with spinal cord injuries, as they demonstrate that this part of the central nervous system is much more plastic than assumed before. Yet, the neurophysiological mechanisms underlying this intrinsic functional plasticity in the spinal cord warrant further investigations.<img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/f_g0Rd4nXj8" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002186Dynamically Allocated Hub in Task-Evoked Network Predicts the Vulnerable Prefrontal Locus for Contextual Memory Retrieval in MacaquesTakahiro Osada et al.info:doi/10.1371/journal.pbio.10021772015-06-30T21:00:00Z2015-06-30T21:00:00Z<p>by Takahiro Osada, Yusuke Adachi, Kentaro Miyamoto, Koji Jimura, Rieko Setsuie, Yasushi Miyashita</p>
Neuroimaging and neurophysiology have revealed that multiple areas in the prefrontal cortex (PFC) are activated in a specific memory task, but severity of impairment after PFC lesions is largely different depending on which activated area is damaged. The critical relationship between lesion sites and impairments has not yet been given a clear mechanistic explanation. Although recent works proposed that a whole-brain network contains hubs that play integrative roles in cortical information processing, this framework relying on an anatomy-based structural network cannot account for the vulnerable locus for a specific task, lesioning of which would bring impairment. Here, we hypothesized that (i) activated PFC areas dynamically form an ordered network centered at a task-specific “functional hub” and (ii) the lesion-effective site corresponds to the “functional hub,” but not to a task-invariant “structural hub.” To test these hypotheses, we conducted functional magnetic resonance imaging experiments in macaques performing a temporal contextual memory task. We found that the activated areas formed a hierarchical hub-centric network based on task-evoked directed connectivity, differently from the anatomical network reflecting axonal projection patterns. Using a novel simulated-lesion method based on support vector machine, we estimated severity of impairment after lesioning of each area, which accorded well with a known dissociation in contextual memory impairment in macaques (impairment after lesioning in area 9/46d, but not in area 8Ad). The predicted severity of impairment was proportional to the network “hubness” of the virtually lesioned area in the task-evoked directed connectivity network, rather than in the anatomical network known from tracer studies. Our results suggest that PFC areas dynamically and cooperatively shape a functional hub-centric network to reallocate the lesion-effective site depending on the cognitive processes, apart from static anatomical hubs. These findings will be a foundation for precise prediction of behavioral impacts of damage or surgical intervention in human brains.<img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/Fn9uFTqtW_Y" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002177Network Hubs in the Brain Have the Biggest Impact on BehaviorJanelle Weaverinfo:doi/10.1371/journal.pbio.10021782015-06-30T21:00:00Z2015-06-30T21:00:00Z<p>by Janelle Weaver</p><img src="http://feeds.feedburner.com/~r/plosbiology/NewArticles/~4/K-nOPvOuon4" height="1" width="1" alt=""/>http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1002178